1. Field of the Invention
The invention relates to a peptide and homologues thereof which inhibit the activity of TGF-β family growth factors in vertebrates, as well as TGF-β-like growth factors in Drosophilia. Specifically, the invention relates to a highly potent fragment of the product of the Drosophilia short gastrulation gene (Sog).
2. History of the Related Art
During vertebrate development growth factors in the TGF-β superfamily control a number of events in tissue differentiation and morphogenesis. Included in the TGF-β superfamily are the bone morphogenic proteins, which promote the growth of new bone tissue and differentiation of osteoblasts. Examples of members of this family of BMPs are BMP-4 and BMP-7, which suppress neurogenesis during early embryonic development and are active in aspects of adult physiology.
BMP-4 has been highly conserved through evolution and has a functional and structural homologue in Drosophilia, known as Dpp. BMP-4 can substitute for Dpp in Drosophilia (Padgett, et al., Proc. Natl. Acad. Sci. USA, 90:2905-2909 (1993)) and Dpp is active in vertebrate tissues (Sampath, et al., Proc. Natl. Acad. Sci. USA, 90:6004-6008 (1993)). In vertebrates, chordin is a high affinity BMP-4 binding protein which inhibits BMP-4 and BMP-7 activity (Sasai, et al., Cell, 779-790 (1994)); in flies, the short gastrulation (Sog) protein inhibits Dpp activity (Francois, et al., Genes & Dev., 8:2602-2616 (1994)). Again chordin and Sog are functional and structural homologues (Schmidt, et al., Development, 121:4319-4328 (1995) and Francois, et al., Cell, 80:19-20 (1995)). In particular, Sog inhibits BMP-4 activity in vertebrates in a manner similar to chordin (Schmidt, et al., id.). It is highly probable that Sog inhibits the activity of other members of the TGF-β family such as BMP-7, which is also inhibited by chordin.
Abnormal activity on the part of BMP-4 has been linked to human cancer, including osteosarcoma and certain leukemias. Interestingly, over-expression of BMP-4 (which is potentiated by BMP-7) has also been shown to stimulate the onset of alopecia (male pattern baldness) in mice, perhaps due to an effect on hair follicle development. Control of such activity can have therapeutic benefit in these and other conditions related to abnormalities in the functioning of TGF-β family growth factors, especially on the part of BMP-4.